(i) Field of the Invention
The present invention relates to a roselipin derivative having an inhibitory activity against diacylglycerol acyltransferase and useful for preventing and treating a disease of a human such as obesity or hyperlipidemia which is caused by accumulation of triacylglycerol.
(ii) Description of the Related Art
Heretofore, several antiobestic drugs and drugs for hyperlipidemia are known. A central anorectic reduces biosynthesis of lipids by suppressing an appetite. However, on the contrary, it may be detrimental to one""s health since it reduces his/her appetite. For this reason, developments of novel antiobestic drug and drug for hyperlipidemia free from side effects have been desired.
In recent years, there is a tendency that along with an improvement in dietary habit, the number of patients suffering from obesity or hyperlipidemia which is caused by accumulation of triacylglycerol has been increasing. This presents a serious problem from the viewpoints of curative medicine and preventive medicine since these diseases cause or induce a variety of lesions. Illustrative examples of diseases which are supervened by obesity or hyperlipidemia caused by accumulation of triacylglycerol include arteriosclerosis, a fatty liver, high blood pressure and diabetes. There is a tendency that the number of patients suffering from these diseases is now increasing.
Obesity is a state of a body in which a deposit fat, especially triglyceride, is accumulated excessively and is caused by abnormal accumulation of fats in fat cells which is ascribable to an increase in synthesis of triacylglycerol. Triacylglycerolemia is also considered to induce lipoproteinemia containing a high level of triacylglycerol in blood due to an increase in synthesis of triacylglycerol in intestines or a liver. Therefore, a substance which inhibits diacylglycerol acyltransferase responsible for selective synthesis of triacylglycerol is expected to suppress accumulation of triacylglycerol and be effective at treating such diseases.
Under the above circumstances, provision of a substance having an inhibitory activity against diacylglycerol acyltransferase is useful for preventing and treating obesity and hyperlipidemia and a variety of adult diseases based on these diseases, as exemplified by arteriosclerosis, a fatty liver, high blood pressure and diabetes.
The present inventors have continuously made a variety of studies on metabolites produced by microorganisms and have newly found that substances having an inhibitory activity against diacylglycerol acyltransferase are produced in a culture of a KF-1040 strain separated from soil and have made an international application for the finding [PCT/JP98/00614(WO99/41265)]. This international application has become U.S. patent application Ser. No. 09/581,660. The present inventors have continued to make studies and succeeded in separating the substances having an inhibitory activity against diacylglycerol acyltransferase from the culture of a KF-1040-strain and purifying the substances. As a result, since the substances having the following chemical structures have heretofore been completely unknown, the substances in the present invention are named as roselipin 1A, roselipin 1B, roselipin 2A and roselipin 2B and named as roselipins as a whole (Tomoda et al., The Journal of Antibiotics, vol. 52, No. 8, pp. 689 to 694, August 1999 and Tabata et al., The Journal of Antibiotics, vol. 9, pp. 815 to 826, September 1999).
The chemical structure of the roselipin 1A is as follows. 
The chemical structure of the roselipin 1B is as follows. 
The chemical structure of the roselipin 2B is as follows. 
The chemical structure of the roselipin 2B is as follows. 
Consequently, the present inventors have succeeded in synthesizing a variety of roselipin derivatives for improving the diacylglycerol acyltransferase inhibiting activity (hereinafter referred to as xe2x80x9cDGAT inhibiting activityxe2x80x9d) of the roselipins. The present invention has been completed based on the finding.
The present invention relates to roselipin derivatives represented by the following formula: 
[wherein R1 represents a hydrogen atom, mannose or acetylated mannose, R2 represents a hydrogen atom or a methyl group, and R3 represents a methyl group or a sugar alcohol]. The roselipin derivatives exclude a compound in which R1 is mannose, R2 is a hydrogen atom and R3 is arabinitol (roselipin 1A or 1B) and a compound in which R1 is acetylated mannose, R2 is a hydrogen atom and R3 is arabinitol (roselipin 2A or 2B).
Further, the present invention relates to derivatives which are compounds selected from the groups consisting of compounds whose groups R1, R2 and R3 comprise a combination of the following substituents.
The roselipin 1A, roselipin 1B, roselipin 2A and roselipin 2B which are starting materials of the roselipin derivatives of the present invention can be obtained as a product obtained by culturing Gliocladium sp. KF-1040 which is a microorganism disclosed in the aforementioned PCT/JP98/00614 (WO99,/41265). The strain has been domestically deposited with National Instituent Bioscience and Technology Agency of Industrial Science and Technology, which is located at 1-3, Higashi 1-chome, Tsukuba-shi, Ibaragi-ken, on Feb. 6, 1998 (Fermentation Research Institute No. P-16629) and then transferred to and internationally deposited with International Patent Organism Depository National Institute of Advanced Industrial Science and Technology, which is located at AIST Tsukuba Central 6, 1-1, Higashi 1-chome, Tsukuba-shi, Ibaraki-ken, Japan, zip. 305-8566, on Feb. 12, 1998 based on BUDAPEST TREATY ON THE INTERNATIONAL RECOGNITION OF THE DEPOSIT OF MICROORGANISMS FOR THE PURPOSE OF PATENT PROCEDURE (Depository No. FERM BP-6251). The above roselipins 1A, 1B, 2A and 2B are obtained in the following manner.